US20090054842A1 - Enhanced penetration system and method for sliding microneedles - Google Patents

Enhanced penetration system and method for sliding microneedles Download PDF

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Publication number
US20090054842A1
US20090054842A1 US10/595,859 US59585904A US2009054842A1 US 20090054842 A1 US20090054842 A1 US 20090054842A1 US 59585904 A US59585904 A US 59585904A US 2009054842 A1 US2009054842 A1 US 2009054842A1
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fluid
microneedles
biological barrier
suction
transport configuration
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US10/595,859
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English (en)
Inventor
Yehoshua Yeshurun
Meir Hefetz
Gil Fruchtman
Yoel Sefi
Yotam Levin
Gilad Lavi
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NanoPass Tech Ltd
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NanoPass Tech Ltd
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Priority to US10/595,859 priority Critical patent/US20090054842A1/en
Assigned to NANOPASS TECHNOLOGIES LTD reassignment NANOPASS TECHNOLOGIES LTD ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: FRUCHTMAN, GIL, HEFETZ, MEIR, LAVI, GILAD, LEVIN, YOTAM, SEFI, YOEL, YESHURUN, YEHOSHUA
Publication of US20090054842A1 publication Critical patent/US20090054842A1/en
Abandoned legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/145—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue
    • A61B5/14507—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue specially adapted for measuring characteristics of body fluids other than blood
    • A61B5/1451—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue specially adapted for measuring characteristics of body fluids other than blood for interstitial fluid
    • A61B5/14514—Measuring characteristics of blood in vivo, e.g. gas concentration, pH value; Measuring characteristics of body fluids or tissues, e.g. interstitial fluid, cerebral tissue specially adapted for measuring characteristics of body fluids other than blood for interstitial fluid using means for aiding extraction of interstitial fluid, e.g. microneedles or suction
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/15—Devices for taking samples of blood
    • A61B5/150007—Details
    • A61B5/150015—Source of blood
    • A61B5/150022—Source of blood for capillary blood or interstitial fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/15—Devices for taking samples of blood
    • A61B5/150007—Details
    • A61B5/150053—Details for enhanced collection of blood or interstitial fluid at the sample site, e.g. by applying compression, heat, vibration, ultrasound, suction or vacuum to tissue; for reduction of pain or discomfort; Skin piercing elements, e.g. blades, needles, lancets or canulas, with adjustable piercing speed
    • A61B5/150061—Means for enhancing collection
    • A61B5/150099—Means for enhancing collection by negative pressure, other than vacuum extraction into a syringe by pulling on the piston rod or into pre-evacuated tubes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/15—Devices for taking samples of blood
    • A61B5/150007—Details
    • A61B5/150206—Construction or design features not otherwise provided for; manufacturing or production; packages; sterilisation of piercing element, piercing device or sampling device
    • A61B5/150236—Pistons, i.e. cylindrical bodies that sit inside the syringe barrel, typically with an air tight seal, and slide in the barrel to create a vacuum or to expel blood
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/15—Devices for taking samples of blood
    • A61B5/150007—Details
    • A61B5/150206—Construction or design features not otherwise provided for; manufacturing or production; packages; sterilisation of piercing element, piercing device or sampling device
    • A61B5/150244—Rods for actuating or driving the piston, i.e. the cylindrical body that sits inside the syringe barrel, typically with an air tight seal, and slides in the barrel to create a vacuum or to expel blood
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/15—Devices for taking samples of blood
    • A61B5/150969—Low-profile devices which resemble patches or plasters, e.g. also allowing collection of blood samples for testing
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/15—Devices for taking samples of blood
    • A61B5/150977—Arrays of piercing elements for simultaneous piercing
    • A61B5/150984—Microneedles or microblades
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/15—Devices for taking samples of blood
    • A61B5/151—Devices specially adapted for taking samples of capillary blood, e.g. by lancets, needles or blades
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/15—Devices for taking samples of blood
    • A61B5/151—Devices specially adapted for taking samples of capillary blood, e.g. by lancets, needles or blades
    • A61B5/15101—Details
    • A61B5/15126—Means for controlling the lancing movement, e.g. 2D- or 3D-shaped elements, tooth-shaped elements or sliding guides
    • A61B5/15128—Means for controlling the lancing movement, e.g. 2D- or 3D-shaped elements, tooth-shaped elements or sliding guides comprising 2D- or 3D-shaped elements, e.g. cams, curved guide rails or threads
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • A61M2037/0023—Drug applicators using microneedles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • A61M2037/003—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles having a lumen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
    • A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
    • A61M2037/0053—Methods for producing microneedles

Definitions

  • the present invention relates to microneedles and, in particular, it concerns an enhanced penetration system and method for sliding microneedles.
  • microneedle arrays have advanced in recent years as part of a system for drug delivery or biological sampling.
  • the microneedle approach shows clear advantages over competing methods of transferring fluids through skin or other barriers.
  • microneedles are painless, allowing shallow delivery to the epidermis.
  • microneedle systems can be self administered or administered by non professionals. Additionally, the potential risk of accidental needle jabs and related injuries is largely avoided.
  • microneedle based devices overcome the molecular size limitations characteristic of conventional transdermal patches, which are inherently limited to small molecules (less than 1,000 dalton and typically less than 300 dalton).
  • microneedles are able to combine the enhancement/penetration mechanism with the drug itself thereby allowing easy application of the drug. Examples of such work may be found in PCT Publications Nos. WO01/66065 and WO 02/17985, both co-assigned with the present application. These publications are hereby incorporated by reference as if set out in their entirety herein. Other relevant publications include WO 99/64580 and WO 00/74763 to Georgia Tech Research Corp., as well as in the following scientific publications: “Micro machined needles for the transdermal delivery of drugs”, S.
  • microneedle array devices do not reliably penetrate the biological barrier, preventing or diminishing cross-barrier transfer of fluids.
  • the transfer is ineffective if the microneedle does not pierce at least the stratum corneum layer.
  • the skin surface is elastic enough to stretch around each microneedle without being pierced. Lack of sharpness of many microneedles exasperates this phenomenon.
  • the fragility, especially under sheer forces, of various microneedle designs limit the penetration force applied to the microneedles, thereby limiting penetration efficacy.
  • many microneedle designs include truncated microneedles. Truncation results in both clogging of the needle channels, and a reduction of sharpness of the needle, again leading to poor penetration and poor material delivery.
  • Ultrasonic vibrations have been a feature of surgical devices intended for use by skilled personnel, but have not been previously applied to enhance penetration of microneedles into a biological barrier.
  • Jet injection depends on a specific positioning of the device relative to the site, and any slight change in that position can end with drug loss or risk of wound (“wet injection”).
  • Two more constraints are high sheer forces applied on the molecules thereby requiring specific validation for each formulation and use of non-standard drug cartridges.
  • penetration through the strong tissue of the upper layers of the skin requires high activation pressures which typically require complex and expensive systems. The use of purely manual pressure for activation may raise questions of reliability.
  • most injectors penetrate to the deep subcutaneous and muscle layers and are incapable of shallow, consistent, delivery in the epidermis or shallow dermis. This may limit their applicability to applications using those locations, for example during vaccination delivery.
  • WO 03/074102 co-assigned with the present application, which is incorporated by reference for all purposes as if fully set forth herein, teaches improved microneedle penetration devices.
  • the device of the aforementioned publication uses directional insertion, preferably using asymmetric microneedles, such as micropyramids (pyramid shaped microneedles with cutting edges or blades), to enhance penetration of the biological barrier.
  • micropyramids pyramid shaped microneedles with cutting edges or blades
  • directional insertion device of the aforementioned publication includes generating a displacement of the microneedle substrate relative to the biological barrier, the displacement having a non-zero component parallel to the surface of the substrate.
  • the in-plane stretching capabilities of the skin are much more limited.
  • FIG. 1 a is an isometric view of a microneedle 10 that is constructed and operable in accordance with the prior art.
  • FIG. 1 b is another isometric view of microneedle 10 of FIG. 1 a .
  • Microneedle 10 has a penetrating tip 12 , a cutting edge 14 and a channel 16 therein.
  • Microneedle 10 is robust, has very thick walls and has a small aspect ratio.
  • Microneedle 10 typically has a height of between 100 and 750 microns, a hole diameter of between 25 and 65 microns and a wall thickness between 20 and 75 microns. Penetrating tip 12 is extremely sharp. Cutting edge 14 enhances penetration of the microneedle by cutting the skin thereby reducing the surface tension of the skin which normally tends to push a microneedle out of the skid.
  • Microneedle 10 is an example of a pyramidal microneedle, generally referred to as a micropyramid. Another example of a pyramidal microneedle is described below, describing the geometry and other advantages of the microneedle in more detail. A tubular microneedle example is also described below.
  • FIG. 2 a is a schematic isometric view of a pyramidal microneedle 18 that is constructed and operable in accordance with the prior art
  • FIG. 2 b is a schematic plan view of microneedle 18 of FIG. 2 a
  • FIG. 2 c is a schematic view of a base-to-tip vector 20 of microneedle 18 of FIG. 2 a
  • FIG. 3 a is a schematic view tubular microneedle 22 that is constructed and operable in accordance with the prior art.
  • FIG. 3 b is a schematic plan view of microneedle 22 of FIG. 3 a FIG.
  • 3 c is a schematic view of a base-to-tip vector 24 of microneedle 22 of FIG. 3 a
  • Microneedle 18 and microneedle 22 are asymmetrical such that base-to-tip vector 20 and base-to-tip vector 24 , respectively, are non-perpendicular to a supporting surface 26 of a substrate 28 .
  • the directionality of the “base-to-tip vector” is then coordinated with the insertion path so as to enhance the penetration effect of the lateral (in-plane) displacement component.
  • the calculation of the “base-to-tip vector” for microneedle 18 and microneedle 22 is illustrated graphically in FIGS. 2 c and 3 c , respectively.
  • the “base-to-tip vector” is typically defined as a vector from a centroid of a base area of the microneedle to a centroid of a penetrating tip of the microneedle.
  • the “centroid” of a shape is a point in the plane of a two-dimensional shape which, when used as an origin, the vector sum over the area of the shape is zero.
  • the centroid corresponds to the center of mass of a thin slice of uniform weight per unit area corresponding to the shape of the cross-section.
  • the base centroid is the centroid of a cross-section of the microneedle form taken in the plane of surface 26 of substrate 28 .
  • the tip centroid is the centroid of the area of a cross-section taken through the microneedle tip parallel to surface 26 .
  • the tip centroid is effectively the sharp point itself.
  • Microneedle 18 is a disclosed in the aforementioned PCT publication no. WO 02/17985, incorporated herein by reference.
  • the base of microneedle 18 is substantially triangular such that the centroid falls somewhere near the intuitive “center” of the triangle.
  • Microneedle 18 has a penetrating tip 30 .
  • Penetrating tip 30 is formed at the intersection of an inclined face with at least one substantially upright wall.
  • the centroid of penetrating tip 30 is defined by the penetrating tip which is located roughly above one of the corners of the triangular base.
  • the resulting base-to-tip vector 20 is illustrated in FIG. 2 c and has a significant in-plane component.
  • the microneedle form of FIG. 2 a is believed to be particularly advantageous for the mechanical support it provides to both the tip and the upright walls which make is highly suited to withstand the directional insertion without breakage.
  • each microneedle is formed with at least two side walls 32 which form a relatively sharp edge 34 between them.
  • a substantially planar face of each side wall is positioned such that an angle between the faces as measured in a plane parallel to the microneedle supporting base surface is no greater than 90 degrees, and preferably between 30 degrees and 70 degrees. It should be noted that the angle mentioned is defined between the substantially planar portions of the faces and does not exclude the possibility of rounding of the edge between the faces. This feature is effective in facilitating cutting of the biological barrier during directional insertion, even where the edge between the faces is somewhat rounded.
  • the direction of insertion is clearly chosen to have a component in the direction in which the cutting edge “points”, and specifically, such that the in-plane component of the insertion direction for at least part of the path of motion lies within the range of angles as illustrated in the plan views of FIGS. 2 b and 3 b.
  • Microneedles having cutting edges allow good penetration of the microneedles across a biological barrier.
  • flexibility of the biological barrier tends to reduce penetration effectiveness even for microneedles having cutting edges, which are also known as micro blades.
  • the present invention is a microneedle device and method of operation thereof.
  • a microneedle device for transporting fluid through a surface of a biological barrier, the device comprising: (a) a fluid transport configuration including: (i) a substrate having a substantially planar surface; and (ii) a plurality of microneedles projecting from the planar surface, each of the microneedles having a cutting edge, a penetrating tip, a base area and a height; (b) an abutment member having at least one abutment surface for abutting the biological barrier, the abutment member being mechanically connected to the fluid transport configuration; and (c) a displacement device operationally connected to the abutment member, the displacement device configured for generating a relative lateral sliding movement between the surface of the biological barrier and the fluid transport configuration in a sliding direction of the microneedles, wherein the microneedles are arranged so that a leading one of the microneedles defines an effective area which is void of another of the microneedles, the
  • a spacing of the microneedles in the sliding direction is at least the square root of 2 times a closest neighbor spacing.
  • the abutment member is configured as a suction cup, the fluid transport configuration being disposed in the suction cup; and (b) the displacement device includes a suction arrangement in fluid connection with the suction cup, the suction arrangement being configured for generating suction for pulling the surface of the biological barrier into the suction cup, the suction cup and the fluid transport configuration being configured such that the surface of the biological barrier slides across the planar surface in the sliding direction.
  • the abutment surface lies on a first plane; (b) the surface of the substrate lies on a second plane; and (c) the first plane is oblique to the second plane.
  • the suction cup has an internal surface which is as asymmetrical.
  • the suction cup includes a side trough in fluid connection with the suction arrangement, the suction arrangement and the side trough being configured such that, after the surface of the biological barrier has made contact with the microneedles, the biological barrier is pulled into the side trough thereby pulling the surface of the biological barrier across the surface of the substrate.
  • the displacement device mechanically links the abutment member and the fluid transport configuration, the displacement device defining a path of movement of the fluid transport configuration relative to the abutment surface, at least part of the path of movement having a non-zero component parallel to the surface of the substrate.
  • the suction arrangement includes a suction plunger, the suction arrangement being configured for generating suction for pulling the surface of the biological barrier into the suction cup with a single one-directional movement of the suction plunger to a retracted position in the suction arrangement.
  • the suction arrangement includes a locking mechanism for retaining the suction plunger in the retracted position.
  • a fluid injection plunger arrangement having a fluid plunger, the fluid injection plunger arrangement being in fluid connection with the fluid transport configuration, such that depressing the fluid plunger delivers the fluid via the fluid transport configuration.
  • the fluid injection plunger arrangement is disposed within the suction arrangement.
  • a priming port in fluid connection with the fluid injection plunger arrangement, the priming port being configured for providing a fluid connection between an external supply of the fluid and the fluid injection plunger arrangement during filling of the fluid injection plunger arrangement with the fluid.
  • the fluid injection plunger arrangement has a movement restriction arrangement configured to prevent negative pressure within the suction cup from pulling down the fluid plunger.
  • At least one of the fluid transport configuration and the abutment member are configured such that, a leading one of the rows of the microneedles contacts the biological barrier prior to a trailing one of the rows of the microneedles contacting the biological barrier.
  • the displacement device is mechanically connected to the abutment member and the fluid transport configuration, the displacement device defining a rotational path of movement of the fluid transport configuration relative to the abutment member.
  • the rotational path of movement is about an axis substantially parallel to the initial orientation of the surface of the biological barrier.
  • a microneedle device for transporting fluid across a biological barrier, the device comprising: (a) a fluid transport configuration including: (i) a substrate having a substantially planar surface; and (ii) a plurality of microneedles projecting from the surface, each of the microneedles having a penetrating tip, a cutting edge, a base area and a height; (b) an abutment member having at least one abutment surface for abutting the biological barrier, and (c) a displacement device mechanically linking the abutment member and the fluid transport configuration, the displacement device defining a path of movement of the fluid transport configuration relative to the abutment surface, at least part of the path of movement having a non-zero component parallel to the planar surface; wherein the microneedles are arranged so that a leading one of the microneedles defines an effective area which is void of another of the microneedles, the effective area being defined as an area marked out
  • a spacing of the microneedles in the direction is at least the square root of 2 times a closest neighbor spacing.
  • a microneedle device for transporting fluid across a biological barrier, the device comprising: (a) a substrate defining a substantially planar surface; and (b) a plurality of microneedles projecting from the surface, each of the microneedles having a penetrating tip, a cutting edge, a base area and a height, each of the microneedles having a base-to-tip vector defined as a vector from a centroid of the base area to a centroid of the penetrating tip, the microneedles being asymmetrical such that the base-to-tip vector is non-perpendicular to the surface, a direction parallel to a projection of the base-to-tip vector on to the planar surface being taken to define a penetration direction, the microneedles being arranged so that a leading one of the microneedles defines an effective area which is void of another of the microneedles, the effective area being defined as an area marked out by translating the base area
  • a spacing of the microneedles in the penetration direction is at least the square root of 2 times a closest neighbor spacing.
  • a microneedle device for transporting fluid through a surface of a biological barrier, the device comprising: (a) a fluid transport configuration including: (i) a substrate having a surface; and (ii) a plurality of microneedles projecting from the surface of the substrate, each of the microneedles having a penetrating tip and a cutting edge, the microneedles being arranged in a plurality of rows; (b) an abutment member having at least one abutment surface for abutting the biological barrier, the abutment member being mechanically connected to the fluid transport configuration; and a (c) displacement device operationally connected to the abutment member, the displacement device configured for generating a relative lateral sliding movement between the fluid transport configuration and the surface of the biological barrier, at least one of the fluid transport configuration and the abutment member being configured such that, a leading one of the rows of the microneedles contacts the biological barrier prior to a trailing one of the
  • the displacement device mechanically links the abutment member and the fluid transport configuration, the displacement device defining a path of movement of the fluid transport configuration relative to the abutment surface, at least part of the path of movement having a non-zero component parallel to the surface of the substrate.
  • the abutment surf lies on a first plane; (b) the surface of the substrate lies on a second plane; and (c) the first plane is oblique to the second plane.
  • the suction cup has an internal surface which is axis asymmetrical.
  • the suction cup includes a side trough in fluid connection with the suction arrangement, the suction arrangement and the side trough being configured such that, after the surface of the biological barrier has made contact with the microneedles, the biological barrier is pulled into the side trough thereby pulling the surface of the biological barrier across the surface of the substrate.
  • a microneedle device for transporting a fluid through a surface of a biological barrier, the device comprising: (a) a fluid transport configuration including: (i) a substrate having a surface; and (ii) a plurality of microneedles projecting from the surface; (b) an abutment member configured as a suction cup having at least one abutment surface for abutting the biological barrier, the fluid transport configuration being disposed in the suction cup; and (c) a displacement device including a suction arrangement in fluid connection with the suction cup, the suction arrangement including a suction plunger, the suction arrangement being configured for generating suction for pulling the surface of the biological barrier into the suction cup with a single one-directional movement of the suction plunger to a retracted position in the suction arrangement.
  • each of the microneedles has a cutting edge and a penetrating tip.
  • the fluid injection plunger arrangement is disposed within the suction arrangement.
  • a priming port in fluid connection with the fluid injection plunger arrangement, the priming port being configured for providing a fluid connection between an external supply of the fluid and the fluid injection plunger arrangement during filling of the fluid injection plunger arrangement with the fluid.
  • the fluid injection plunger arrangement has a movement restriction arrangement configured to prevent negative pressure within the suction cup from pulling down the fluid plunger.
  • a microneedle device for transporting fluid through a surface of a biological barrier, the device comprising: (a) a fluid transport configuration including: a (i) substrate having a surface; and (ii) a plurality of microneedles projecting from the surface; (b) an abutment member having at least one abutment surface for abutting the biological barrier; and (c) a displacement device mechanically connected to the abutment member and the fluid transport configuration, the displacement device defining a rotational path of movement of the fluid transport configuration relative to the abutment member.
  • the rotational path of movement is about an axis substantially parallel to the initial orientation of the surface of the biological barrier.
  • each of the microneedles has a cutting edge and a penetrating tip.
  • FIG. 1 a is an isometric view of a microneedle that is constructed and operable in accordance with the prior art
  • FIG. 1 b is another isometric view of the microneedle of FIG. 1 a;
  • FIG. 2 a is a schematic isometric view of a pyramidal microneedle that is constructed and operable in accordance with the prior art
  • FIG. 2 b is a schematic plan view of the microneedle of FIG. 3 a;
  • FIG. 2 c is a schematic view of a base-to-tip vector of the microneedle of FIG. 2 a;
  • FIG. 3 a is a schematic view tubular microneedle that is constructed and operable in accordance with the prior art
  • FIG. 3 b is a schematic plan view of the microneedle of FIG. 3 a;
  • FIG. 3 c is a schematic view of a base-to-tip vector of the microneedle of FIG. 3 a;
  • FIG. 4 is a schematic isometric view of a fluid transport configuration that is constructed and operable in accordance with a preferred embodiment of the present invention
  • FIG. 5 is a schematic side view of a fluid transport configuration that is constructed and operable in accordance with an alternate embodiment of the present invention
  • FIG. 6 is a schematic side view of a microneedle device including the fluid transport configuration of FIG. 4 ;
  • FIG. 7 is a schematic side view of a microneedle device including the fluid transport configuration of FIG. 5 ;
  • FIG. 8 a is an axial sectional view of a microneedle device including the fluid transport configuration of FIG. 5 ;
  • FIG. 8 b is an exploded view of the microneedle device of FIG. 8 a;
  • FIG. 8 c is a view of the microneedle device of FIG. 8 a after fluid is drawn therein;
  • FIG. 8 d is a view of the microneedle device of FIG. 8 c after the biological barrier pulled therein;
  • FIG. 8 e is an expanded view of the lower section of the microneedle device of FIG. 8 d;
  • FIG. 8 f is a view of the microneedle device of FIG. 8 d after the fluid is delivered through the surface of the biological barrier;
  • FIG. 9 is a cross-sectional view of a microneedle device employing the concept of the fluid transport configuration of FIG. 5 ;
  • FIG. 10 is a cross-sectional view of a microneedle device including the fluid transport configuration of FIG. 4 ;
  • FIG. 11 a is an isometric view of a microneedle device which is constructed and operable in accordance with a preferred embodiment of the present invention
  • FIG. 11 b is a plan view of the device of FIG. 11 a;
  • FIG. 11 c is a cross-sectional view through line A-A of FIG. 11 b prior to use of the device;
  • FIG. 11 d is a cross-sectional view through line B-B of FIG. 11 b prior to use of the device;
  • FIG. 11 e is a cross-sectional view through line A-A of FIG. 11 b showing the device in an intermediate position;
  • FIG. 11 f is a cross-sectional view through line A-A of FIG. 11 b showing the device in a final position;
  • FIG. 11 g is an expanded view of region B of FIG. 11 c showing the device prior to insertion into the biological barrier;
  • FIG. 11 h is an expanded view of region C of FIG. 11 f showing the device inserted into the biological barrier;
  • FIG. 11 i is a partial cross-sectional view of a microneedle device prior to insertion into the biological barrier having microneedles facing the opposite direction to that of the device of FIG. 11 a ;
  • FIG. 11 j is a view of the microneedle device of FIG. 11 i inserted into the biological barrier.
  • the present invention is a microneedle device and method of operation thereof.
  • WO 03/074102 co-assigned with the present application, teaches improved microneedle penetration devices using directional insertion, preferably using asymmetric microneedles, to enhance penetration of the biological barrier. It is explained in the aforementioned publication that the flexibility of the skin is particularly pronounced under out-of-plane deformations, allowing the skin to be locally depressed so as to conform to the external shape of the microneedles without allowing proper penetration. This effect seriously impedes, or even prevents, fluid transfer via the microneedles.
  • the directional insertion device includes generating a displacement of the microneedle substrate surface relative to the biological barrier, the displacement having a non-zero component parallel to the surface of the substrate.
  • Directional insertion represents a great improvement over other existing microneedle insertion devices. Nevertheless, it has been found that the penetration effect or the directional insertion device can be improved. Particularly, it has been found that the penetration and/or cutting effectiveness (if the microneedle has a cutting edge) of a leading microneedle in an array is reduced by a trailing microneedle in the same array, due to tension release created by the trailing needle on the biological barrier.
  • the above problem is not limited to the first row of microneedles in an array, but to every row of microneedles in an array which has another row of microneedles trailing behind it.
  • the above problem is removed or greatly reduced by either arranging the microneedles using a specific layout, as will be explained in more detail with reference to FIG. 4 , and/or by ensuring that a leading row of microneedles makes contact with the biological barrier before a trailing row of microneedles makes contact with the biological barrier, as will be explained in more detail with reference to FIG. 5 .
  • Fluid transport configuration 40 includes a substrate 42 defining a substantially planar surface 44 .
  • Fluid transport configuration 40 also includes a plurality of microneedles 46 projecting from surface 44 .
  • Each microneedle 46 is a micropyramid having a cutting edge 48 , a penetrating tip 50 , a height 52 and a base area 54 .
  • Height 52 is the height of the microneedle as measured perpendicularly from surface 44 .
  • Height 52 is typically the shortest distance from penetrating tip 50 to surface 44 .
  • Each microneedle 46 has a base-to-tip vector defined as a vector from a centroid of base area 54 to a centroid of penetrating tip 50 .
  • the term “base-to-tip” vector has been defined herein above with reference to FIGS. 2 c and 3 c .
  • Microneedles 46 are asymmetrical such that their base-to-tip vector is non-perpendicular to surface 44 .
  • a direction parallel to a projection of the base-to-tip vector on to surface 44 is taken to define a penetration direction, T.
  • Microneedles 46 are arranged in rows perpendicular to penetration direction, T. In order to reduce or eliminate the pulling effect of a trailing microneedle on a leading microneedle, microneedles 46 are arranged so that a leading microneedle 47 defines an effective area 49 behind leading microneedle 47 which is void of another microneedle. Area 49 is defined by the area marked out by translating base area 54 of leading microneedle 47 by height 52 of leading microneedle 47 in a direction opposite to penetration direction, T.
  • the microneedle spacing in penetration direction T is at least the square root of 2, times the closest neighbor spacing.
  • spacing is defined as the distance between centroids of the base areas of the microneedles.
  • Fluid transport configuration 70 includes a substrate 72 having a surface 74 .
  • Fluid transport configuration 70 also includes a plurality of microneedles 76 projecting from surface 74 .
  • Each microneedle 76 is a micropyramid having a cutting edge 78 and a penetrating tip 80 .
  • Microneedles 76 are arranged in a plurality of rows 82 .
  • Fluid transport configuration 70 is generally included as part of a of a directional insertion device (not shown). Suitable directional insertion devices are described with reference to FIGS. 7 to 11 i .
  • the directional insertion device defines a path of motion of fluid transport configuration 70 such that the path of motion has a component, N, perpendicular to a surface 84 of a biological barrier 86 and a component parallel to surface 84 in penetration direction, T. Therefore, the directional insertion device generates a relative lateral sliding movement between fluid transport configuration 70 and surface 84 of biological barrier 86 .
  • the term “relative lateral sliding movement” is defined to include either movement of fluid transport configuration 70 across surface 84 of biological barrier 86 or movement of surface 84 of biological barrier 86 across a stationary fluid transport configuration 70 or a combination of both.
  • FIG. 7 is a schematic side view of a microneedle device 102 including fluid transport configuration 70 of FIG. 5 .
  • Microneedle device 102 is substantially the same as the directional insertion devices taught with reference to WO 03/074102 except for the differences described hereinbelow.
  • Microneedle device 102 includes an abutment member 108 having at least one abutment surface 110 for abutting a surface 104 of a biological barrier 106 .
  • Microneedle device 102 includes a displacement device 112 mechanically linking abutment member 108 and fluid transport configuration 70 .
  • Displacement device 112 defines a path of movement of fluid transport configuration 70 relative to abutment surface 110 .
  • FIG. 8 a is an axial sectional view of a microneedle device 114 including fluid transport configuration 70 of FIG. 5 .
  • FIG. 8 b is an exploded view of device 114 of FIG. 8 a
  • Device 114 is a suction device configured for bringing a surface 118 of a biological barrier 116 into contact with microneedles 76 of fluid transport configuration 70 so that leading row 88 of microneedles 76 contacts surface 118 of biological barrier 116 prior to trailing row 90 of microneedles 76 contacting surface 118 of biological barrier 116 .
  • microneedles 76 anchor a region of surface 118 of biological barrier 116 .
  • the free portion of biological barrier 116 (in other words, the portion of biological barrier 116 not restricted by the anchoring effect) is pulled further into suction cup 122 thereby stretching surface 118 and creating a lateral sliding movement between microneedles 76 of leading row 88 as these microneedles 76 cut surface 118 .
  • Surface 118 is then anchored by the next row of microneedles 76 and the skin is pulled by the suction and stretched and the anchored microneedles 76 cut surface 118 . This process continues until biological barrier 116 fills the cavity of suction cup 122 as shown best in FIG.
  • Device 114 also includes a fluid injection plunger arrangement 134 having a fluid plunger 136 .
  • Fluid injection plunger arrangement 134 is disposed within suction arrangement 128 so that fluid injection plunger arrangement 134 and suction arrangement 128 share a common wall of plunger housing 132 .
  • Fluid injection plunger arrangement 134 and suction arrangement 128 form a coaxial arrangement. This coaxial arrangement has many advantages, including ease of use whereby suction of biological barrier 116 and injection of fluid into biological barrier 116 can be performed with the same hand.
  • Fluid injection plunger arrangement 134 is in fluid connection with fluid transport configuration 70 such that depressing fluid plunger 136 delivers the fluid via microneedles 76 of fluid transport configuration 70 . Priming of fluid injection plunger arrangement 134 is described in more detail with reference to FIG. 8 c . Injection of the fluid is described with reference to FIG. 8 f.
  • FIG. 8 c is a view of device 114 of FIG. 8 a after the fluid is drawn therein.
  • Device 114 also includes a priming port 138 disposed in the side of abutment member 120 .
  • a regular syringe having a prefixed dose of medication is brought into contact with priming port 138 .
  • Printing port 138 is configured for providing a fluid connection between the regular syringe (an external supply of the fluid) and fluid injection plunger arrangement 134 during filling of fluid injection plunger arrangement 134 with the fluid.
  • Fluid injection plunger arrangement 134 has a movement restriction arrangement 140 configured to prevent negative pressure within suction cup 122 from pulling fluid plunger 136 toward suction cup 122 and thereby dispensing the fluid before biological barrier 116 has been penetrated by microneedles 76 .
  • Movement restriction arrangement 140 includes a projection 142 projecting radially from fluid plunger 136 . Once fluid plunger 136 has been retracted projection 142 engages into a recess 144 in plunger housing 132 thereby preventing negative pressure in suction cup 122 from pulling fluid plunger 136 . Projection 142 is released from recess 144 by pushing on the handle of fluid plunger 136 with a force greater than a minimum threshold value.
  • Fluid injection plunger arrangement 134 also includes another projection 146 projecting radially from fluid plunger 136 .
  • Projection 146 moves longitudinally within a slot 148 disposed within plunger housing 132 in order to prevent rotation of fluid plunger 136 within plunger housing 132 . This rotation could neutralize the functionality of movement restriction arrangement 140 .
  • projection 146 also ensure proper positioning of fluid plunger 136 in fluid injection plunger arrangement 134 .
  • Suction arrangement 128 includes a locking mechanism 150 for retaining suction plunger 130 in a retracted position.
  • Locking mechanism 150 includes two resilient arms 152 .
  • Resilient arms 152 are stored within plunger housing 132 while suction plunger 130 is depressed (best seen in FIG. 8 c ).
  • resilient arms 152 are released from plunger housing 132 so that resilient arms 152 expand.
  • Suction plunger 130 cannot be pulled into plunger housing 132 as resilient arms 152 rest on the top surface of plunger housing 132 thereby preventing downward movement of suction plunger 130 .
  • Locking mechanism 150 also controls the suction level required for optimal operation of device 114 . Due to effects of fatigue in plastics, resilient arms 152 are kept under low (below 25% of yield) stress during shelf life to maintain their flexibility.
  • FIG. 8 f is a view of device 114 of FIG. 8 d after the fluid is delivered through surface 118 of biological barrier 116 .
  • the fluid is delivered by depressing fluid plunger 136 .
  • resilient arms 152 are compressed thereby allowing suction plunger 130 to be depressed for releasing the suction on biological barrier 116 .
  • FIG. 9 is a cross-sectional view of a lower section of a microneedle device 154 employing the concept of fluid transport configuration 70 of FIG. 5 .
  • Device 154 is substantially the same as device 114 of FIGS. 8 a - f except for the following differences.
  • Device 154 has a suction cup 156 which has an abutment surface 158 .
  • Device also has a suction arrangement 176 .
  • Device 154 has a fluid transport configuration 160 including a substrate 178 having a surface 180 .
  • Surface 180 has a plurality of microneedles 162 disposed thereon. Each microneedle 162 includes a penetrating tip and a cutting edge.
  • suction cup 156 ensures that the pulling force on a surface 168 of a biological barrier 170 is uneven. Therefore, when biological barrier 170 is pulled in to suction cup 156 via the suction, a leading row of microneedles 162 contacts surface 168 before a trailing row of microneedles 162 contacts surface 168 . Additionally, the anchoring and stretching effects of biological barrier 170 as described with reference to device 114 also occur with device 154 . Parenthetically, suction cup 122 of device 114 also has an axis asymmetrical suction cup 122 caused by slating fluid transport configuration 70 . Nevertheless, biological barrier 116 is pulled evenly by device 114 until it makes contact with fluid transport configuration 70 as the lower portion of suction cup 122 is symmetrical.
  • Suction cup 156 also includes a side trough 174 in fluid connection with suction arrangement 176 .
  • Suction arrangement 176 and side trough 174 are configured so that suction arrangement 176 pulls biological barrier 170 via side trough 174 . Therefore, after surface 168 of biological barrier 170 has made contact with microneedles 162 , biological barrier 170 is pulled into side trough 174 thereby pulling surface 168 of biological barrier 170 across surface 180 of substrate 178 .
  • FIG. 10 is a cross-sectional view of a lower section of a microneedle device 182 including fluid transport configuration 40 of FIG. 4 .
  • Device 182 includes an abutment member 184 including a suction cup 186 having an abutment surface 188 for abutting a surface 190 of a biological barrier 192 .
  • Fluid transport configuration 40 is disposed in suction cup 186 so that the surface of fluid transport configuration 40 lies on a plane which is parallel to a plane defined by abutment surface 188 .
  • Suction cup 186 has a side trough 196 .
  • Device 182 includes a suction arrangement 194 in fluid connection with side trough 196 of suction cup 186 .
  • Device 198 is designed for continuous delivery of fluid or where it is impossible to maintain suction of the biological barrier for a long time.
  • pressure below the surface of the biological barrier mainly due to the fluid being injected, tries to eject the microneedles from the biological barrier. This problem is more pronounced for shorter microneedles, and pyramidal microneedles, in particular.
  • Device 198 reduces the problems associated with this below surface pressure, by ensuring that the microneedles are inserted at an inclined angle to the normal surface of the biological barrier, as will be described below. Therefore, the pressure below the surface of the biological barrier is effectively neutralized.
  • Device 198 includes a fluid transport configuration 200 including a substrate 202 having a surface 204 .
  • Fluid transport configuration 200 also includes a plurality of microneedles 206 projecting from surface 204 .
  • Each microneedles 206 has a cutting edge and a penetrating tip.
  • Device 198 includes an abutment member 208 having an abutment surface 210 for abutting the biological barrier.
  • Abutment surface 210 is typically attached to the biological barrier using a suitable adhesive or clamping device (not shown). Adhesion can be achieved by the use of a wide range of adhesives or adhesive tapes which are designed for use in medical applications, as are well known in the-art.
  • abutment surface 210 substantially encircles fluid transport configuration 200 on three sides. This creates a convex shaped pocket of the biological barrier.
  • Projections 222 are disposed close to the end of block 216 having fluid transport configuration 200 thereon.
  • Abutment member 208 includes two slots 224 . Slots 224 extend almost parallel to a plane lying on abutment surface 210 . Projections 222 are configured for sliding along slots 224 . The degree of parallelism of slots 224 with the plane of abutment surface 210 is used to control how fluid transport configuration 200 approaches the skin.
  • the joint between block 214 and block 216 is depressed.
  • fluid transport configuration 200 moves through a rotational and linear path.
  • displacement device 212 defines a rotational path of movement of fluid transport configuration 200 relative to abutment member 208 about an axis substantially parallel to the initial orientation of the surface of the biological barrier.
  • rotational path is defined herein to include the possibility of linear motion with rotation motion.
  • substantially parallel is defined as within 30 to 60-degrees of the initial orientation of the surface of the biological barrier.
  • initial orientation of the surface is defined as the initial orientation of the surface of the biological barrier before the surface of the barrier is moved or stretched or flexed by device 198 .
  • FIG. 11 c A single push of displacement device 212 in the direction of an arrow 226 , moves fluid transport configuration 200 through a rotation path.
  • Displacement device 212 also includes a connection 230 to a reservoir (not shown) for storing the fluid for injecting.
  • Connection 230 is typically a tube or any other common connection such as a luer connector.
  • An arrow 228 depicts the direction of flow of the fluid through displacement device 212 into fluid transport configuration 200 .
  • the fluid is typically driven by an infusion pump.
  • FIG. 11 e is a cross-sectional view through line A-A of FIG. 11 b showing device 198 in an intermediate position of displacement device 212 .
  • FIG. 11 f is a cross-sectional view through line A-A of FIG. 11 b showing device 198 in a final position
  • FIG. 11 f shows the in-use position of device 198 where the fluid is injected through microneedles 206 of fluid transport configuration 200 .
  • Displacement device 212 is self-locking due to the geometry of displacement device 212 .
  • device 198 is a low-profile device making it suitable for long-term fluid-transfer use.
  • FIG. 11 g is an expanded view of region B of FIG. 11 c showing device 198 prior to insertion into a biological barrier 232 .
  • FIG. 11 h is an expanded view of region C of FIG. 11 f showing the device 198 inserted into biological barrier 232 .
  • Microneedles 206 anchor the surface of biological barrier 232 as displacement device 212 starts to rotate ( FIG. 11 g ). Displacement device 212 rotates creating a “step” in biological barrier 232 . Microneedles 206 penetrate into the vertical surface of the “step” FIG. 11 h ).
  • Microneedles 206 are disposed on surface 204 so that a cutting edge 234 of microneedles 206 is facing into the surface of biological barrier 232 .
  • the direction that cutting edge 234 faces affects two factors. First, the effect of pressure of the biological barrier trying to eject the microneedles. Second, fluid leakage along the microneedles sloping sides.
  • the above embodiment has cutting edge 234 facing into the surface of biological barrier 232 thereby reducing fluid leakage.
  • FIG. 11 i is a partial cross-sectional view of a microneedle device 236 prior to insertion into the biological barrier having microneedles 238 facing the opposite direction to that of device 198 of FIG. 11 a
  • FIG. 11 j is a view of device 236 of FIG. 11 i inserted into the biological barrier.
  • Each microneedle 238 has a cutting edge 240 .
  • Microneedles 238 are disposed so that the cutting edge faces toward the surface of the biological barrier thereby canceling the effect of pressure acting as an ejector of the microneedles.
US10/595,859 2003-11-18 2004-11-18 Enhanced penetration system and method for sliding microneedles Abandoned US20090054842A1 (en)

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EP1699524A4 (de) 2009-07-15
WO2005049107A3 (en) 2005-11-10

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